This is a single-center, single-arm, open-label, dose-escalation, early-phase 1 study to evaluate the safety, tolerability and preliminary efficacy of ZZSW-01 injection in patients with relapsed/refractory B-cell malignancies.

This investigator-initiated clinical study aims to evaluate ZZSW-01 injection, the extracellular vesicle vector that carries CD19 CAR mRNA, in patients with relapsed/refractory B-cell hematologic malignancies. Under this design, eligible subjects will receive multiple injections. The study adopts a dose-escalation design to assess safety, tolerability, and preliminary efficacy.

Inclusion Criteria:

Participants must meet all of the following inclusion criteria:

1. Age ≥18 years, no restriction on sex.

2. ECOG (Eastern Cooperative Oncology Group) performance status score of 0-2.

3. Expected survival ≥3 months.

4. Histologically or cytologically confirmed CD19-positive relapsed or refractory B-cell malignancies according to the WHO classification of lymphoid neoplasms, including:

   Relapsed/refractory B-NHL: patients who have failed at least two prior lines of therapy, are intolerant to the toxicity of second-line regimens, or are not eligible for autologous stem cell transplantation, including but not limited to diffuse large B-cell lymphoma (DLBCL) not otherwise specified, DLBCL/high-grade B-cell lymphoma with MYC and BCL2 rearrangements, high-grade B-cell lymphoma not otherwise specified, primary mediastinal B-cell lymphoma, mantle cell lymphoma, grade 3b follicular lymphoma, and transformed large B-cell lymphoma from indolent B-NHL.

   Relapsed/refractory precursor B-ALL: patients who relapse after achieving CR following second-line therapy, or who fail to achieve CR/CRi after completion of second-line therapy.

5. For relapsed/refractory B-NHL: at least one measurable lesion as assessed by the investigator (e.g., lymph node with long axis >15 mm, or extranodal lesion with long axis >10 mm).

   For relapsed/refractory precursor B-ALL: baseline bone marrow blasts ≥5%.

6. Adequate organ function as defined below (no administration of blood components or hematopoietic growth factors within 14 days prior to first dosing):

   Hematology:

   Relapsed/refractory B-NHL: ANC ≥1.5×10^9/L, platelets ≥75×10^9/L, hemoglobin ≥70 g/L, absolute CD8+ T-cell count ≥0.3×10^9/L; if bone marrow involvement is present: ANC ≥1.0×10^9/L, platelets ≥50×10^9/L, hemoglobin ≥70 g/L.

   Relapsed/refractory precursor B-ALL: ANC ≥1.0×10^9/L (G-CSF support permitted), platelets ≥50×10^9/L (no platelet transfusion within 7 days), hemoglobin ≥80 g/L (no RBC transfusion within 7 days); if bone marrow involvement or not in remission: ANC ≥0.5×10^9/L (G-CSF support permitted), platelets ≥30×10^9/L (no platelet transfusion within 7 days), hemoglobin ≥70 g/L (no RBC transfusion within 7 days). Additionally, absolute CD8+ T-cell count ≥0.2×10^9/L and CD19+ B-cell percentage ≤5%.

   Liver function: TBIL ≤1.5×ULN; ALT and AST ≤2.5×ULN (≤5×ULN if liver metastases are present).

   Renal function: Serum creatinine ≤1.5×ULN (if >1.5×ULN, creatinine clearance must be ≥50 mL/min).

   Coagulation: INR ≤1.5×ULN and APTT ≤1.5×ULN; patients on anticoagulation may be included if INR ≤2.5×ULN.

   Oxygenation: Oxygen saturation >92% on room air.

7. Non-hematologic toxicities from prior therapies (except disease-related) have resolved to ≤grade 1 before enrollment (excluding alopecia and ≤grade 2 neurotoxicity from chemotherapy).

8. Women of childbearing potential must have a negative serum pregnancy test within 7 days prior to ZZSW-01 infusion. All fertile male and female participants must agree to use effective contraception during the study and for at least 6 months after the last dose. (Definition of women of childbearing potential and contraceptive methods are detailed in Appendix 1.)

9. Ability and willingness to provide written informed consent and to comply with study procedures, follow-up assessments, and treatment.

Exclusion Criteria

Participants meeting any of the following conditions will be excluded from this study:

1. Patients with CNS involvement of B-cell malignancies confirmed by lumbar puncture and/or MRI with CNS-related symptoms.

2. Patients with isolated extramedullary relapse of B-ALL.

3. Patients with severe hereditary diseases or congenital hematopoietic dysfunction.

4. Patients with Burkitt's lymphoma/leukemia or blast phase chronic myeloid leukemia (p210 BCR-ABL+).

5. Current or past history of central nervous system disorders, including: seizures, ischemic/hemorrhagic cerebrovascular disease, paralysis, aphasia, stroke, severe brain injury, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, psychiatric illness, or any autoimmune disease involving the CNS.

6. Receipt of chemotherapy within 2 weeks prior to ZZSW-01 infusion (except intrathecal chemotherapy for prevention of CNS leukemia, which must be stopped ≥1 week prior to infusion).

7. Prior systemic immune checkpoint inhibitor therapy (e.g., anti-PD-1/PD-L1 mAbs) within fewer than 3 half-lives before ZZSW-01 infusion; or other systemic antitumor therapy within fewer than 2 weeks or 5 half-lives (whichever is shorter) before infusion.

8. Use of systemic therapeutic corticosteroids within 72 hours prior to ZZSW-01 infusion (physiologic replacement doses are allowed, e.g., prednisone <10 mg/day or equivalent).

9. Receipt of targeted therapies or antibody drugs (including BiTEs, antibody-drug conjugates) within 2 weeks, or cytotoxic therapy within 1 week prior to ZZSW-01 infusion.

10. Autologous stem cell transplantation (ASCT) within 6 weeks prior to ZZSW-01 infusion.

11. Any prior allogeneic hematopoietic stem cell transplantation (allo-HSCT).

12. Known history of the following diseases:

    1. . Systemic vasculitis (e.g., Wegener's granulomatosis, polyarteritis nodosa)
    2. Systemic lupus erythematosus (SLE)
    3. . Active or uncontrolled autoimmune diseases (e.g., Crohn's disease, rheumatoid arthritis, autoimmune hemolytic anemia)
    4. . Primary or secondary immunodeficiency (e.g., HIV infection or severe infectious diseases)

13. Evidence of any of the following infections:

    1. . Chronic or active hepatitis B (HBV) infection (except HBcAb-positive with HBV DNA <500 IU/mL)
    2. . Hepatitis C virus (HCV) infection
    3. . Human immunodeficiency virus (HIV) infection
    4. . Syphilis infection

14. Major surgery within 4 weeks prior to screening, if deemed unsuitable for enrollment by the investigator.

15. Concurrent active malignancy. (Patients with prior malignancies cured ≥2 years may be eligible).

16. Any of the following cardiac conditions:

    1. . Left ventricular ejection fraction (LVEF) ≤45% (by echocardiography)
    2. . NYHA class III or IV congestive heart failure
    3. . Severe arrhythmia requiring treatment, including QTc ≥450 ms in males or ≥470 ms in females (QTcB=QT/RR1/2)
    4. . Uncontrolled hypertension (systolic ≥140 mmHg and/or diastolic ≥90 mmHg), pulmonary hypertension, or unstable angina
    5. . Myocardial infarction, bypass surgery, or stent placement within 12 months prior to dosing
    6. . Clinically significant valvular heart disease
    7. . Any other cardiac disease deemed unsuitable by the investigator

17. Lymphoma involving the atrium or ventricle.

18. Clinical emergencies caused by obstruction or compression from lymphoma masses at screening (e.g., bowel obstruction, vascular compression).

19. History of deep vein thrombosis or pulmonary embolism within 6 months prior to screening.

20. Hypersensitivity (allergy to ≥2 drugs or foods), or known hypersensitivity to components of the investigational product (compound electrolyte injection, 5% human serum albumin).

21. Receipt of live vaccines within 6 weeks prior to screening.

22. Uncontrolled active infection at screening (e.g., sepsis, bacteremia, fungemia, viremia).

23. Participation in another interventional clinical trial with investigational drugs within 3 months prior to ZZSW-01 infusion, or intent to participate in another clinical trial or receive non-protocol antitumor therapy during the study.

24. Any other condition that, in the judgment of the investigator, renders the patient unsuitable for participation.